Adhesions are abnormal deposits of fibrous tissue that form within the peritoneal cavity. Abdominal adhesions are a common cause of small bowel obstruction and female infertility [1-3]. Adhesion formation occurs after any surgical procedure. However, it is extremely common after abdominal and pelvic operations and remains a source of considerable morbidity. The incidence ranges from about 67%-93% after general surgical abdominal operations and up to about 97% after open gynecologic pelvic procedures [4, 5]. In clinical and autopsy studies of patients who had prior laparotomy, the incidence of intra-abdominal adhesions was about 70-90% [6]. Use of both absorbable polyglycolic acid meshes and non-absorbable polypropylene meshes as reinforcing materials in surgery is associated with a high incidence of adhesion formation [6a, 6b].
Factors associated with the formation of post-surgical adhesions include trauma, thermal injury, infection, ischemia and foreign bodies. Other factors associated with adhesion formation include tight suturing where tension within the sutured peritoneum produces ischemia and abrasion. Exposure to foreign bodies such as talc and powders from the gloves, lint from abdominal packs or disposable papers items may also contribute to the formation of adhesions [7-9]. Neutropenia is associated with lower rates of adhesion and may play a role in modulating post-operative adhesion [10].
The peritoneum is composed of two mesothelial sheets that enclose predominantly adipocytes embedded in loose connective tissue, and also aggregates of mononuclear phagocytic cells. The greater omentum is the largest part of the peritoneum with the size varying from 300 gm to 2000 gm and a surface area of 300 cm2 to 1500 cm2. The omentum has a rich vascular supply with numerous characteristic capillary convolutions that are termed omental glomeruli due to their similarity with renal glomeruli. These capillary beds lie directly under the mesothelium [11]. Adhesions are formed as a result of fibrous repair of peritoneal injury mostly after surgery.
Milky spots develop as specific structures in the greater omentum of the peritoneum between the 20th and 35th week of gestation [12]. They are corpuscles found in the omental glumeruli measuring 0.1-2 mm in size, hardly visible to the naked eye, and under low magnification look like tufts of cotton wool [13, 14]. Milky spots are characterized by a permanent glomus pattern of vascular structure, specific cellular population and a specialized mesothelial lining. In humans, milky spots comprise of macrophages (70%), B-lymphocytes (10%), T-lymphocytes (10%), mast cells, and stromal cells. The mean number of cells in one milky spot is approximately 600 [15]. The number of milky spots is highest in infancy and gradually decreases with age [12]. The activation of milky spot, which occurs within 6 hours of abdominal surgery plays a role in adhesion formation [16].
The macrophages in the mature omentum are essentially scavengers. They appear to differentiate from monocytic precursors in the milky spots and are not dependent on precursors derived from the bone marrow [17]. They are dendritic in shape and have marked phagocytic abilities. They avidly phagocytose intraperitoneally injected carbon particles and bacteria. When activated, the macrophage precursors in the milky spots proliferate, migrate to the mesothelial surface, and transform into dendritic-shaped macrophages. Following surgery, macrophages increase in number and change function which are different from the resident macrophages and secrete variable substances including cycloxygenase and lipoxygenes metabolites, plasminogen activator, plasminogen activator inhibitor (PAI) etc [9, 18]. These macrophages recruit new mesothelial cells that proliferate forming islands in the injured areas resulting in peritoneal remesothelialization. Following stimulation of the milky spot there is an increased microvascular permeability to fluid, neutrophils, monocytes and fibrin deposits within the connective tissue matrix of milky spots, and subsequent increased cellular migration across the mesothelial lining into the peritoneal cavity [19].
Adhesion formation begins with injury inflicted on the peritoneum whether by an injurious stimuli including bacterial, chemical toxicity, ischemia, mechanical or simply drying from exposure [16, 25]. The injury leads to an inflammatory response, which progresses to fibrin deposition and subsequent fibrinous adhesion. If the fibrinous adhesion is not degraded within the first days of injury, reparative cells including fibroblasts are propagated into the fibrin matrix turning it into permanent fibrous adhesion. This process is completed within a week of the injury. The balance of fibrin deposition and breakdown is therefore crucial in the early phase of peritoneal repair and adhesion formation [25-27]. Peritoneal macrophages may be involved in regulation of plasmin activity in the peritoneal cavity [28], and thus a role in adhesion formation [29].
Various methods of adhesion prevention and treatment have been employed, including prevention of fibrin deposition in the peritoneal exudate, reduction of local tissue inflammation, and removal of fibrin deposits. Most of the existing methods inhibit one of these categories and yet have limited success. Implants in the form of resorbable fabrics or membranes (which are thought to act as macrophage barriers) as well as gels formed of biocompatible materials have also been employed to reduce formation of adhesions. Examples are the products sold under the trademarks INTERCEED and SEPRAFILM.
Glutamine is a conditional essential amino acid which the body is unable to synthesize in sufficient quantities under certain physiologic circumstances [30, 31] such as major surgery, shock, traumatic injury and severe sepsis. A decrease in extracellular glutamine impairs the function of macrophages and other immune cells, resulting in increased protein degradation from skeletal muscle [20]. Macrophages are extremely active cells (10 times per minute based on ATP turnover and 5 times a minute based on oxygen consumption) with a high capacity to take up glutamine and ‘trap it’ as glutamate, which acts as an intracellular store for both energy formation and provision of precursors for biosynthesis. Mouse peritoneal macrophages have been shown to utilize a high amount of glutamine via the process of glutaminolysis even though they are seen as terminally differentiated cells [21, 22]. These macrophages are characterized by high rate of protein secretion and membrane recycling [23, 24]. Although glutamine constitutes >50% of the unbound amino acid pool in human skeletal muscle, rapid reduction in blood and tissue glutamine has been noted following catabolic events such as major surgery [32], trauma [33], and sepsis [34, 35].
Glutamine is safe, well absorbed, and has no documented side effects. Glutamine is known to enhance wound healing. Glutamine and its dipeptides have been used for parenteral and enteral supplementation components in critically ill patients. A recent study by Fukuzawa, et al. [36] concluded that glutamine enhances both phagocytosis and the production of Reactive Oxygen Intermediates (ROI) by neutrophils in post-operative patients. In a randomized prospective study, Morlion et al. using glutamine dipeptides in total parenteral nutrition (TPN) concluded that the supplement group had shorter hospital stay, improved immune status and nitrogen balance after abdominal surgery [37].
Alanyl-glutamine and glycyl-glutamine are two dipeptides of glutamine which have been employed clinically due to their higher solubility and chemical stability over free glutamine, making them more stable sources of the constituent amino acids [37-42]. Enteral supplementation with alanyl-glutamine but not glutamine+alanine mixture promotes intestinal adaptation as evidenced by increased peptide transport after intestinal resection [43]. Alanyl-glutamine also prevents intestinal damage, as demonstrated by increased peptide transport expression and an elevated plasma glutamine concentration after CPM administration [44]. Alanyl-glutamine alone was recently used enterally in post-operative patients for the first time with reported success and safety [53].